Piperazine-substituted pyridazinone derivatives useful as glucan synthase inhibitors

Abstract

There is disclosed a method for treating or preventing fungal infections comprising the administration of at least one glucan synthase inhibitor of a formula as described above in the specification or a pharmaceutically acceptable salt thereof; also claimed are methods of preparing pharmaceutical compositions comprising a compound as described above in the specification and a carrier, method of treating or preventing fungal infections comprising administration of combinations of glucan synthase inhibitor of a formula as described above in the specification and other antifungal agents, and method of treating or preventing fungal infections comprising administration of pharmaceutical compositions prepared according to a method described above in the specification, and a method of preparing a kit in a single package of the above described pharmaceutical composition and other antifungal agents.

1 . The use of at least one compound of a formula selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and the pharmaceutically acceptable salts and hydrates thereof, for the manufacture of a medicament for treating or preventing fungal infections in an animal or plant in need of such treatment or prevention. 
   
   
       2 . The use of  claim 1  wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and the pharmaceutically acceptable salts and hydrates thereof. 
   
   
       3 . The use of  claim 1  wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     the pharmaceutically acceptable salts and hydrates thereof. 
   
   
       4 . The use of  claim 1  wherein said at least one compound is used for the manufacture of a medicament to treat or prevent infections from yeasts or moulds. 
   
   
       5 . The use of  claim 4  wherein yeasts are selected from the group comprising  Candida, Cryptococcus, Pichia, Rhodotorula, Saccharomyces  and  Trichosporon , and moulds are selected from the group comprising  Absidia, Alternaria, Apophysomyces, Aspergillus, Bjerkandera, Blastomyces, Coccidioides, Cunninghamella, Exophiala, Fusarium, Histoplasma, Microsporum, Mucor, Paecilomyces, Penicillium, Pseudallescheria, Ramichloridium, Rhizomucor, Rhizopus, Saksenaea, Scedosporium, Sporothrix, Trichophyton  and  Wangiella.    
   
   
       6 . The use of  claim 1  wherein the animal is a mammal, a fish, a bird, a crustacean or a reptile. 
   
   
       7 . The use of  claim 1  wherein the animal is a human. 
   
   
       8 . The use of  claim 1  wherein at least one compound as defined in  claim 1  is used to treat or prevent infections from  Microsporum  or  Malassezia.    
   
   
       9 . The use of  claim 8  wherein at least one compound as defined in  claim 1  is used to treat or prevent growth of the fungal pathogens selected from the group comprising  Alternaria, Aphanomyces, Ascophyta, Biploaris, Botrytis, Cercospora, Claviceps, Cochlioobolus, Colletotrichum, Erysiphe, Gibberella, Glomerella, Gomyces, Guignardia, Helminthosporium, Leptosphaeria, Magnaporthe, Microdochium, Monolinia, Mycosphaerella, Nectria, Penicillium, Plasmopara, Podosphaera, Puccinia, Pyrenophora, Pyricularia, Pythium, Phytophthora, Rhizoctonia, Sclerotina, Sclerotium, Septoria, Sphaerotheca, Thielaviopsis, Tilletia, Uncinula, Urocystis, Ustilago, Venturia  and  Verticillium.    
   
   
       10 . The method of preparing a pharmaceutical composition comprising combining at least one compound as defined in  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       11 . The method of  claim 10  further comprising adding an additional antifungal agent. 
   
   
       12 . The method of  claim 11  wherein the additional antifungal agent is selected from the group consisting of azoles, echinocandins, polyenes, allylamines, thiocarbamates, nikkomycins, pradimicins, 5-fluorocytosines, oxaboroles, ciclopiroxolamine, griseofulvin, and morpholines. 
   
   
       13 . The method of  claim 12  wherein the additional antifungal agent is selected from the group consisting of fluconazole, miconazole, itraconazole, voriconazole, posaconazole, caspofungin, micafungin, anidulafungin, amphotericin B, liposomal formulations of amphotericin B, nystatin, terbinafine, tolnaftate, nikkomycin, pradimicin, 5-fluorocytosine, oxaborole, ciclopiroxolamine, griseofulvin, and fenpropimorph. 
   
   
       14 . The use of  claim 1  wherein said medicament further comprises one or more additional antifungal agents. 
   
   
       15 . The use of  claim 14  wherein the additional antifungal agent is selected from the group consisting of azoles, echinocandins, polyenes, allylamines, thiocarbamates, nikkomycins, pradimicins, 5-fluorocytosines, oxaboroles, ciclopiroxolamine, griseofulvin, and morpholines. 
   
   
       16 . The use of  claim 14  wherein the additional antifungal agent is selected from the group consisting of fluconazole, miconazole, itraconazole, voriconazole, posaconazole, caspofungin, micafungin, anidulafungin, amphotericin B, liposomal formulations of amphotericin B, nystatin, terbinafine, tolnaftate, nikkomycin, pradimicin, 5-fluorocytosine, oxaborole, ciclopiroxolamine, griseofulvin, and fenpropimorph. 
   
   
       17 . The method of preparing a kit for treating or preventing fungal infections comprising in a single package, one container comprising one or more compounds as defined in  claim 1  in a pharmaceutically acceptable carrier, and one or more separate containers, each comprising one or more additional antifungal agent in a pharmaceutically acceptable carrier. 
   
   
       18 . The use of the pharmaceutical composition as defined in  claim 10  for the manufacture of a medicament for treating or preventing fungal infections in an animal or plant. 
   
   
       19 . The use of the pharmaceutical composition as defined in  claim 11  for the manufacture of a medicament for treating or preventing fungal infections. 
   
   
       20 . The use of the pharmaceutical composition as defined in  claim 12  for the manufacture of a medicament for treating or preventing fungal infections. 
   
   
       21 . The use of the pharmaceutical composition as defined in  claim 13  for the manufacture of a medicament for treating or preventing fungal infections. 
   
   
       22 . The use of  claim 1 , wherein said use is for treating or preventing growth of fungal pathogens on inanimate surface. 
   
   
       23 . The use of  claim 22 , wherein said medicament further comprises one or more additional antifungal agents. 
   
   
       24 . The use of at least one compound listed in  claim 1  or a pharmaceutically acceptable salt, or hydrate thereof, for the manufacture of a medicament for inhibiting one or more glucan synthase.